Thienocycloheptapyridazine compounds and their pharmaceutical use

ABSTRACT

A thienocycloheptapyridazine compound of the formula ##STR1## wherein R stands for hydrogen, a halogen or a C 1-4  alkyl, Ar stands for an aryl, a heteroaryl, or an aryl or a heteroaryl having as a substituent at least a halogen, a C 1-4  alkyl, a C 1-4  alkoxy, nitro, amino, hydroxy, trifluoromethyl and/or a C 2-5  alkanoylamino; and the bond   between 4-position and 42-position represents a single bond or a double bond, which is useful as an antianxiety agent, amnesia-treating drug, a brain function-activating drug or an antidementiac drug.

TECHNICAL FIELD

This invention relates to thienocycloheptapyridazine compounds which arenovel and of use as pharmaceuticals, and to their pharmaceutical use.

BACKGROUND ART

Benzodiazepine, (BZP) ,derivatives represented by diazepam have been usefor a long as an antianxiety drug or a therapeutic medicine for sleepdisturbance. The recent pharmacological studies have shown that thereexist receptors which exhibit a specific affinity for BZP derivatives inthe central nervous system [Science, vol. 198, 849 (1977)]. In thestudies and researches conducted subsequently, there have beeninvestigated and developed not only BZP derivatives but also compoundswhich have structures different from BZP but exhibit a high affinity forBZP receptors and a BZP-like action (BZP agonist), compounds whichexhibit a high affinity for BZP receptors but exhibit a pharmacologicalaction the reverse of BZP (BZP inverse agonist), and compounds whichexhibit a high affinity for BZP receptors but nevertheless exhibit nopharmacological activity themselves and rather show an antagonisticaction against the action of the agonist or the inverse-agonist (BZPantagonist) [Advance in Drug Research, vol. 14, 165 (1985)].

Since BZP derivatives which are used as an antianxiety drug have asedative action, a muscle-relaxing action and an anticonvulsive actionin addition to an antianxiety action, they often cause troubles in termsof side effects such as dizziness and sleepiness. Thus, researches ofnon-BZP types of compounds aiming at developing selective antianxietydrugs with less side effects are thriving. Nevertheless, there have notbeen found satisfactory ones yet.

Also, in recent years, amnesia-inducing actions by BZP agonists werefound [Nature, vol. 321, 864 (1986)], and there have been reportssuggesting the possibility that BZP-antagonists exhibiting anantagonistic action against the amnesic actions induced by BZP agonists,and BZP-inverse-agonists exhibiting an action reverse to the amnesicactions by BZP agonists, are usable as brain-function activating drugs.[Trends in Neurosciences, vol. 11, 13 (1988)].

In the meantime, in the specification of U.S. Pat. No. 4,602,019 thereare disclosed compounds such as 2,4,4a,5-tetrahydro-7-(1H-imidazol-1-yl)-3H-indeno[1,2-c]pyridazin-3-one having a cardiacaction and an antihypertensive action. The Journal of MedicinalChemistry, vol. 24, 830 (1981) discloses compounds such as2-(4-chlorophenyl)benzothiopyrano-[4,3-c]pyrazol-3-one possessing animmune-supressing action.

DISCLOSURE OF INVENTION

The present inventors have conducted intensive studies for the purposeof developing BZP-agonists, BZP-inverse-agonists or BZP-antagonistshaving a non-BZP-nucleus which are useful pharmaceuticals, and providingeffective compounds and pharmaceuticals.

It has been found that the above-mentioned purpose can be attainedaccording to the present invention described hereinafter.

That is, the first invention is to provide thienocycloheptapyridazinecompounds of the formula ##STR2## wherein R stands for hydrogen, ahalogen or a C₁₋₄ alkyl, Ar stands for an aryl, a heteroaryl, or an arylor a heteroaryl having as a substituent at least a halogen, a C₁₋₄alkyl, a C₁₋₄ alkoxy, nitro, amino, hydroxy, trifluoromethyl and/or aC₂₋₅ alkanoylamino; and the bond between 4-position and 4a-positionrepresents a single bond or a double bond.

The second invention is to provide pharmaceutical compositionscomprising a thienocycloheptapyridazine compound of the above formula(I).

The symbols of the formula (I) and each of the below-mentioned formulaeare defined in detail below. The halogen represents chlorine, bromine,fluorine or the like; the C₁₋₄ alkyl represents methyl, ethyl, propyl,isopropyl, butyl, isobutyl or tert-butyl; the C₁₋₄ alkoxy representsmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy;the C₂₋₅ alkanoylamino represents acetylamino, propionylamino,butyrylamino or pivaloylamino; the aryl represents phenyl, naphthyl orthe like; and the heteroaryl represents a 5- or 6-membered ring or itsfused ring containing 1 to 3 (preferably 1 or 2) hetero atom(s) (e.g.nitrogen, oxygen, sulfur) on the ring such as 2-, 3-, or 4-pyridyl, 2-or 3-thienyl, 3- or 4-pyrazolyl, 1- or 2-imidazolyl, 2-, 4- or5-pyrimidinyl, 3-, 4- or 5-pyridazinyl or 2-, 4- or 5-benzimidazolyl.

Preferable compounds of the present invention are the compounds selectedfrom the group consisting of2-(4-chlorophenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-(4-methylphenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-phenyl-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-(4-methoxyphenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridizin-3-one,2-(4-chlorophenyl)-2,5,6,7-tetrahydro-9-methyl-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridizin-3-one,2-(6-chloro-2-pyridyl)-2,4,4a,5,6,7-hexahydro-3H-thieno]2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-(4-methylphenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-(4-methoxyphenyl)-2,4,4a-5,6,7-hexahydro-3-H-thieno[2',3':6,7]cyclohepta-[1,2-c]pyridazin-3-one,9-bromo-2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,9-bromo-2-(4-methoxyphenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-oneand9-bromo-2-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one.

The compounds of the formula (I) can be produced by subjecting toring-closure reaction a compound of the formula ##STR3## wherein each ofthe symbols is as defined above, which can be obtained by reacting acompound of the formula ##STR4## wherein R is as defined above, with ahydrazine derivative of the formula

    Ar--NHNH.sub.2                                             (III)

wherein Ar is defined as above or its acid addition salt.

The reactions proceed by heating under reflux in a suitable solvent, forexample, an alcohol solvent such as methanol, ethanol or propanol, orinert solvent such as benzene or toluene for 5 to 20 hours to yield thecompound of the formula (I) and the compound of the formula (IV).

In case where an acid addition salt of the hydrazine derivative of theformula (III) is employed, the reaction is conducted in the presence ofan acid scavenger (sodium acetate, potassium acetate, sodiumbicarbonate, sodium carbonate, potassium carbonate, pyridine,triethylamine, etc.).

When the compound of the formula (IV) is obtained in the above reaction,the compound of the formula (I) can be produced by heating the obtainedcompound of the formula (IV) under reflux in acetic acid for 5-10 hours.

The compound of the formula (I) wherein the bond between 4-position and4a-position is a double bond can be synthesized also by adding brominein an amount of 1-1.5 times mol dropwise to the corresponding compoundof the formula (I) wherein the bond between 4-position and 4a-positionis a single bond, in acetic acid as the solvent at 20°-60° C. [Journalof Medicinal Chemistry, vol. 14, 262 (1971)], or by reacting thecompound of the formula (I) wherein the bond between 4-position and4a-position is a single bond with sodium-m-nitrobenzenesulfonate(Bachmann method, The specification of United Kingdom Patent No.1168291).

The compounds of the formula (I) which can be produced in theabove-mentioned manner can be isolated and purified by a conventionalmethod such as column chromatography or recrystallization.

The compounds of the formula (II) of this invention are novel compoundswhich have not been described in any literature. The compounds can beproduced by, for example, converting the corresponding compounds of theformula ##STR5## wherein R is as defined above, or their acid additionsalts to their quaternary ammonium compounds by adding methyl iodide tothe compounds of the formula (V) or their acid addition salts in acetoneand retaining the mixture at room temperature for 2-5 hours, followed byconverting the quaternary ammonium compounds to the corresponding cyanocompounds of the formula ##STR6## wherein R is as defined above, byadding potassium cyanide or sodium cyanide to the quaternary ammoniumcompounds in an aqueous methanol and reacting the mixture at 30°-50° C.for 4-10 hours, followed by adding the thus-obtained compounds of theformula (VI) to acetic acid and conc. hydrochloric acid and heating themixture reflux under for 5-12 hours.

For reference sake, representative examples of the compounds of theformula (II) are indicated with their physical constant below.

2-Methyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-5-aceticacid, melting at 155.5°-157.5° C.

4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-5-acetic acid,melting at 130°-131° C.

2-Bromo-4-oxo-5,6,7,8-tetrahydro 4H-cyclohepta[b]thiophene-5-aceticacid, melting at 129°-131° C.

The compounds of the formula (I) exhibit a high affinity of 10⁻⁸ -10⁻⁹ Mto BZP receptors and have an antagonistic action against chemicalconvulsants such as bicuculline and pentylenetetrazole. They alsoexhibit an inhibitory action against amnesia induced byelectroconvulsive shock.

The pharmacological actions of the compounds of the present inventionare shown with the experimental methods therefor below.

EXPERIMENTAL EXAMPLE 1 : DISPLACEMENT ABILITY FOR BENZODIAZEPINE

The experiment for specific affinity to benzodiazepine receptors wascarried out in accordance with the method described in Life Science,vol. 20, 2101 (1977).

The crude cynaptosome fraction was isolated from the cerebral cortex ofmale Wistar rats aged 9-10 weeks, and was suspended in 50 mMTris-hydrochloric acid buffer solution (pH 7.4) containing 120 mM sodiumchloride and 5 mM potassium chloride. These suspensions were used forthe experiment.

The test compounds in several different concentrations and tritiateddiazepam (in final concentration of 2 nM) were added to the synaptosomesuspensions, and the mixtures were incubated at 0° C. for 20 minutes.These suspensions were filtered with Whatman GF/B glassfiber filters.After the filters were washed with the above-mentioned buffer solution,the radioactivity left on the filters was measured with the use of aliquid scintillation counter.

Specific binding was determined by subtracting binding in the presenceof 10⁻⁶ M unlabelled diazepam from total binding.

According to the foregoing experimental method, the binding force tobenzodiazepine receptors of the compound of the present invention isevaluated from its displacement ability for tritiated diazepam at itsbinding site, which is represented by Ki value (nM).

The results of the experiment are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Test compound Affinity to BZP Receptors,                                      (Example No.) Ki (nM)                                                         ______________________________________                                        1             4.8                                                             4             1.1                                                             ______________________________________                                    

EXPERIMENTAL EXAMPLE 2 : ANTI-BICUCULLINE ACTION

The anti-bicuculline action test was carried out in accordance with themethod described in Life Science, vol. 21, 1779 (1977).

Male ddY mice weighing 20-28 g, 7-14 animals per group, were used. Onehour after the oral administration of the test compounds, (+)bicuculline was intravenously administered at the dosage of 0.6 mg/kg,and 50% effective concentration (ED₅₀) was estimated by examiningwhether tonic convulsion within 5 minutes was caused or not. The resultwas that the ED₅₀ values of the compounds of Example 1 and 5 were 8.1mg/kg and 9.8 mg/kg, respectively.

EXPERIMENTAL EXAMPLE 3 : ACTION ON EXPERIMENTAL AMNESIA

Twenty male ddY mice were used per group to investigate the action ofthe test compounds on learning and memory ability of amnesia-inducedmice by observing a step-through passive avoidance reflex.Amnesia-induced animals were prepared by applying electroconvulsiveshock (ECS) soon after the acquisition trial and the retention test wascarried out 24 hours after the acquisition trial. Test compounds wereadministered intraperitoneally (i.p.) 30 minutes before the acquisitiontrial.

As the result, it was found that the compound of Example 4 significantlyprolonged the latency time in the trial of the retention test at thedose of 2.5 mg/kg (i.p.) or more and exhibited an improvement action onamnesia.

EXPERIMENTAL EXAMPLE 4 : ACUTE TOXICITY

Five male ddY mice were used per group. The mice were administered with300 mg/kg of the compound of Example 4 intraperitoneally, but all micesurvived for 5 days after the administration. Similarly, the mice wereorally administered with 1000 mg/kg of the compound, but they survivedfor 5 days after the administration.

As apparent from the foregoing various pharmacological studies includingexperiments, the compounds (I) of the present invention have a highaffinity for BZP receptors and exhibit an antagonistic action againstchemical convulsion-inducing agents such as bicuculline andpentylenetetrazole, whereas they influence to a small extent somaticfunctions such as muscle relaxing actions. Thus, they are useful as anantianxiety agent. Also, since they possess an inhibitory action onamnesia induced by electroconvulsive shock, they are useful as anamnesia-treating drugs, brain function-activating drugs andantidementiac drugs. They are also of value as an antidote for excessiveadministration of or toxicosis by existent antianxiety drugs such asdiazepam.

When the compounds of the formula (I) are used as pharmaceuticals, atherapeutically effective amount of the compounds and adequatepharmacologically acceptable additives such as excipient, carrier,diluent and so on are mixed to be formulated into a form such astablets, capsules, granules, syrups, injectable solutions,suppositories, dispersible powders or the like and are administered in aform mentioned above. The dosage, for example, in the case of oraladministration, is generally about 5-500 mg daily per adult, which isadministered once a day or in divided doses several times a day.

Below, this invention is more specifically described with workingexamples, which are not to be construed as limitative.

EXAMPLE 1

A suspension of 2.5 g of2-methyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-5-aceticacid and 1.95 g of 4-chlorophenyl hydrazine in 50 ml of toluene isrefluxed under heating for 4 hours. After cooling, the mixture isconcentrated under reduced pressure and the precipitated crystals arerecrystallzed from ethanol to give 2.7 g of2-(4-chlorophenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 119°-121° C.

EXAMPLE 2

The reaction and procedure are conducted in the same manner as inExample 1 using 4-methylhydrazine in place of 4-chlorophenylhydrazine asused in Example 1 to give2-(4-methylphenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 117°-119° C.

EXAMPLE 3

The reaction and procedure are conducted by the same method as ofExample 1 using phenylhydrazine instead of 4-chlorophenylhydrazine asused in Example 1 to give2-phenyl-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 102°-103° C.

EXAMPLE 4

The reaction and procedure are conducted by the same method as ofExample 1 using 4-methoxyphenylhydrazine in place of4-chlorophenylhydrazine as used in Example 1 to give2-(4-methoxyphenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 136°-138.5° C.

EXAMPLE 5

To a solution of 3.6 g of2-(4-chlorophenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-onein 30 ml of acetic acid is added 0.6 ml of bromine at 40° C. withstirring and the reaction mixture is stirred at 40-45° C. for 30minutes. The mixture is poured into water and the resultant oil iscollected by decantation. The crude product is subjected to columnchromatography on silica gel and eluted with chloroform to give 1.27 gof2-(4-chlorophenyl)-2,5,6,7-tetrahydro-9-methyl-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 149.5°-151° C.

EXAMPLE 6

A suspension of 2.0 g of4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-5-acetic acid and 1.6g of 4-chlorophenylhydrazine in 40 ml of ethanol is refluxed underheating for 8 hours. After cooling, the mixture is concentrated underreduced pressure and the ethanol is distilled off. The residue isdissolved in 40 ml of acetic acid and the solution is refluxed underheating for 2 hours. After distilling off the acetic acid under reducedpressure, the resultant residue is subjected to column chromatography onsilica gel. The crystals obtained from the fraction which has beeneluted with chloroform are recrystallized from a mixed solvent ofchloroform and ethanol to give 2.0 g of2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-pyridazin-3-oneas pale brown crystals, melting at 156°-158° C.

The following compounds can be obtained in the same manner as in theabove examples.

EXAMPLE 7

2-(6-Chloro-2-pyridyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 165°-167° C.

EXAMPLE 8

2-(4-Methylphenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 105°-107° C.

EXAMPLE 9

2-(4-Methoxyphenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 135°-137° C.

EXAMPLE 10

9-Bromo-2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 129°-131° C.

EXAMPLE 11

9-Bromo-2-(4-methoxyphenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,melting at 139°-141° C.

EXAMPLE 12

To a solution of 2.5 g of9-bromo-2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-onein 40 ml of acetic acid is added a solution of 1.1 g of bromine in 5 mlof acetic acid with stirring at 40° C. over a period of 10 minutes. Themixture is stirred at 40°-50° C. for 20 minutes and poured into ice-coldwater. The precipitated crystals are collected by filtration, washedwith water, dissolved in chloroform and subjected to columnchromatography on silica gel. The crystals obtained from the fractionwhich has been eluted with chloroform are recrystallized from a mixedsolvent of ethanol and chloroform to give 1.5 g of9-bromo-2-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-oneas white crystals, melting at 143°-144° C.

The compounds shown in the following tables can be obtained in the samemanner as in the above examples.

    ______________________________________                                         ##STR7##                                                                     No.    R        Ar                4-4a bond                                   ______________________________________                                        13     9-CH.sub.3                                                                              ##STR8##         S                                           14     9-CH.sub.3                                                                              ##STR9##         D                                           15     9-CH.sub.3                                                                              ##STR10##        S                                           16     9-CH.sub.3                                                                              ##STR11##        D                                           17     9-CH.sub.3                                                                              ##STR12##        S                                           18     9-CH.sub.3                                                                              ##STR13##        D                                           19     9-CH.sub.3                                                                              ##STR14##        S                                           20     9-CH.sub.3                                                                              ##STR15##        D                                           21     9-CH.sub.3                                                                              ##STR16##        S                                           22     9-CH.sub.3                                                                              ##STR17##        D                                           23     9-CH.sub.3                                                                              ##STR18##        S                                           24     9-CH.sub.3                                                                              ##STR19##        D                                           25     9-CH.sub.3                                                                              ##STR20##        S                                           26     9-CH.sub.3                                                                              ##STR21##        D                                           27     9-CH.sub.3                                                                              ##STR22##        S                                           28     9-CH.sub.3                                                                              ##STR23##        D                                           29     H                                                                                       ##STR24##        S                                           30     H                                                                                       ##STR25##        D                                           31     H                                                                                       ##STR26##        D                                           32     H                                                                                       ##STR27##        S                                           33     H                                                                                       ##STR28##        D                                           34     H                                                                                       ##STR29##        S                                           35     H                                                                                       ##STR30##        D                                           36     H                                                                                       ##STR31##        D                                           37     H                                                                                       ##STR32##        D                                           38     H                                                                                       ##STR33##        S                                           39     H                                                                                       ##STR34##        D                                           40     H                                                                                       ##STR35##        S                                           41     H                                                                                       ##STR36##        D                                           42     H                                                                                       ##STR37##        S                                           43     H                                                                                       ##STR38##        D                                           44     H                                                                                       ##STR39##        S                                           45     H                                                                                       ##STR40##        D                                           46     H                                                                                       ##STR41##        S                                           47     H                                                                                       ##STR42##        D                                           48     9-Br                                                                                    ##STR43##        S                                           49     9-Br                                                                                    ##STR44##        D                                           50     9-Br                                                                                    ##STR45##        S                                           51     9-Br                                                                                    ##STR46##        D                                           52     9-Br                                                                                    ##STR47##        S                                           53     9-Br                                                                                    ##STR48##        D                                           54     9-Br                                                                                    ##STR49##        S                                           55     9-Br                                                                                    ##STR50##        D                                           56     9-Br                                                                                    ##STR51##        S                                           57     9-Br                                                                                    ##STR52##        D                                           58     9-Br                                                                                    ##STR53##        S                                           59     9-Br                                                                                    ##STR54##        D                                           60     9-Br                                                                                    ##STR55##        S                                           61     9-Br                                                                                    ##STR56##        D                                           ______________________________________                                         S: single bond, D: double bond                                           

FORMULATION EXAMPLE

Tablets containing 10 mg of a compound of the formula (I) are preparedin accordance with the following formulation.

    ______________________________________                                        Compound of formula (I)                                                                           10.0       mg                                             Lactose             58.5       mg                                             Corn starch         25.0       mg                                             Crystalline cellulose                                                                             20.0       mg                                             Polyvinylpyrrolidone K-30                                                                         2.0        mg                                             Talc                4.0        mg                                             Magnesium stearate  0.5        mg                                                                 120.0      mg                                             ______________________________________                                    

The compound of the formula (I) is pulverized by an atomizer into finepowders below 10μ in average particle diameter, which are admixed withlactose, corn starch and crystalline cellulose sufficiently in akneading machine, and further kneaded with polyvinylpyrrolidone paste.The kneaded mixture is passed through a sieve of 200 mesh, dried at 50°C. and passed through a sieve of 24 mesh. Talc and magnesium stearateare mixed therewith and the mixture is compressed into 120.0 mg tabletswith a punch of 8 mm in diameter. These tablets are, if desired,subjected to sugar-coating or film-coating.

While the present invention has been adequately and sufficientlydescribed in the foregoing specification including examples, thedescription can be changed or modified within the spirit and scope ofthis invention.

We claim:
 1. A thienocycloheptapyridazine compound of the formula##STR57## wherein R is hydrogen, halogen or C₁₋₄ alkyl; Ar is a memberselected from the group consisting of phenyl, naphthyl, pyridyl,thienyl, pyrazolyl, imidazolyl, pyrimidinyl, pyridazinyl andbenzimidazolyl, which Ar is unsubstituted or substituted by a memberselected from the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,nitro, amino, hydroxy, trifluoromethyl and C₂₋₅ alkanoylamino; and thebond between the 4-position and 4a-position is a single bond or a doublebond.
 2. A compound as claimed in claim 1 which is selected from thegroup consisting of2-(4-chlorophenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-(4-methylphenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-phenyl-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-(4-methoxyphenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-(4-chlorophenyl)-2,5,6,7-tetrahydro-9-methyl-3-H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]-cyclohepta[1,2-c]pyridazin-3-one,2-(6-chloro-2-pyridyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta-[1,2-c]pyridazin-3-one,2-(4-methylphenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-pyridazin-3-one,2-(4-methoxyphenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one,9-bromo-2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]-cyclohepta[1,2-c]pyridazin-3-one,9-bromo-2-(4-methoxyphenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-oneand9-bromo-2-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one.3. A pharmaceutical composition comprising a compound as claimed inclaim 1 or 2 and a pharmaceutically acceptable additive.
 4. A method oftreating a patient having anxiety, which comprises administering to thepatient an antianxiety effective amount of a compound as claimed inclaim 1 or
 2. 5. A method of treating a patient having amnesia, whichcomprises administering to the patient an antiamnesia effective amountof a compound as claimed in claim 1 or 2.